RT Journal Article
T1 Mapping the malaria parasite drug-able genome using in vitro evolution and chemogenomics
A1 Cowell, Annie
A1 Istvan, Eva
A1 Lukens, Amanda
A1 Gomez-Lorenzo, Maria
A1 Vanaerschot, Manu
A1 Sakata-Kato, Tomoyo
A1 Flannery, Erika
A1 Magistrado, Pamela
A1 Abraham, Matthew
A1 LaMonte, Gregory
A1 Williams, Roy
A1 Franco, Virginia
A1 Linares Gómez, María
A1 Arriaga, Ignacio
A1 Bopp, Selina
A1 Corey, Victoria
A1 Gnädig, Nina
A1 Coburn-Flynn, Olivia
A1 Reimer, Christin
A1 Gupta, Purva
A1 Murithi, James
A1 Fuchs, Olivia
A1 Sasaki, Erika
A1 Kim, Sang
A1 Teng, Christine
A1 Wang, Lawrence
A1 Willis, Paul
A1 Siegel, Dionicio
A1 Tanaseichuk, Olga
A1 Zhong, Yang
A1 Zhou, Yingyao
A1 Ottilie, Sabine
A1 Gamo, Francisco-Javier
A1 Lee, Marcus
A1 Goldberg, Daniel
A1 Fidock, David
A1 Wirth, Dyann
A1 Winzeler, Elizabeth
AB Chemogenetic characterization through in vitro evolution combined with whole-genome analysis can identify antimalarial drug targets and drug-resistance genes. We performed a genome analysis of 262 Plasmodium falciparum parasites resistant to 37 diverse compounds. We found 159 gene amplifications and 148 nonsynonymous changes in 83 genes associated with drug-resistance acquisition, where gene amplifications contributed to one-third of resistance acquisition events. Beyond confirming previously identified multidrug-resistance mechanisms, we discovered hitherto unrecognized drug target–inhibitor pairs, including thymidylate synthase and a benzoquinazolinone, farnesyltransferase and a pyrimidinedione, and a dipeptidylpeptidase and an arylurea. This exploration of the P. falciparum resistome and druggable genome will likely guide drug discovery and structural biology efforts, while also advancing our understanding of resistance mechanisms available to the malaria parasite.
PB American Association for the Advancement of Science
SN 0036-8075
YR 2018
FD 2018
LK https://hdl.handle.net/20.500.14352/93565
UL https://hdl.handle.net/20.500.14352/93565
LA eng
NO Cowell AN, Istvan ES, Lukens AK, Gomez-Lorenzo MG, Vanaerschot M, Sakata-Kato T, et al. Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics. Science 2018;359:191–9. https://doi.org/10.1126/science.aan4472.
NO Bill and Melinda Gates Foundation
NO The National Institutes of Health
NO The National Institute of Allergy and Infectious Diseases
NO The National Institute of General Medical Sciences
DS Docta Complutense
RD 4 abr 2025